A synovial sarcoma (also known as malignant synovioma) is a rare form of soft tissue cancer, and usually occurs near to the joints of the arm, neck or leg. Despite the propensity of some sarcomas to arise adjacent to joints, synovial sarcomas are not necessarily synovial in nature. In fact, synovial sarcomas have been documented in most human tissues and organs, including the brain, prostate and heart, most commonly in the extremities of young adults.
Synovial sarcoma occurs most commonly in the young, representing about 8-10% of all soft tissue sarcomas and about 15-20% of cases in adolescents and young adults. The peak of incidence is before the age of 30, with a ratio of 1.2:1 for males-to-females. The presentation of synovial sarcomas usually comprises an otherwise asymptomatic swelling or mass, sometimes accompanied by fatigue.
Synovial sarcoma is uniquely characterized by the balanced chromosomal translocation t(X,18; p11.2,q11.2), which is demonstrable in virtually all cases of synovial sarcomas and not found in any other human neoplasms. This translocation creates an in-frame fusion of the SS18 gene to SSX1 or SSX2, whereby all but the C-terminal eight amino acids of SS18 become fused to the C-terminal 78 amino acids of the SSX partner. An analogous translocation of SSX4 is detected in less than 1% of cases. This recurrent aberration leads to the fusion of two proteins, SS18 (SYT) and SSX (SSX1, SSX2, or SSX4), generating an oncogene that is necessary for synovial sarcoma initiation and propagation.
The mammalian nucleosome remodeling SWI/SNF complex (known in humans as “BRG1- or HRBM-associated factors” or BAF complex) is a group of proteins that tightly associate to remodel the way DNA is packaged. It is composed of several proteins mammalian versions of products of the yeast SWI and SNF genes (SWI1, SWI2/SNF2, SWI3, SWI5, SWI6), as well as other polypeptides. The BRG subunit of the complex has DNA-stimulated ATPase activity, and the complex can destabilize histone-DNA interactions in reconstituted nucleosomes in an ATP-dependent manner. The BAF complex acts as a tumor suppressor in many human cancers, and is mutated in about 20% of human malignancies. In synovial sarcomas, the SS18-SSX fusion protein integrates as a stable member of the BAF complex, replacing the product of the wild-type allele, the SS18 subunit, causing dramatic changes in the complex composition, including the ejection and degradation of the core subunit BAF47 (SNF5) from the complex.
Treatment of synovial sarcomas generally involves surgery, chemotherapy and radiotherapy, in view of the fact that no on-target biologics have been developed to date. Surgery to remove the tumor and surrounding tissue is curative in approximately 20-70% of patients. Conventional chemotherapy, such as doxorubicin hydrochloride and ifosfamide, reduces the number of remaining microscopic cancer cells, but its benefit for overall survival remains unclear. Radiotherapy is thought to reduce the chance of local recurrence. However, the disease is prone to early and late recurrences, and the ten-year disease-free survival rate remains on the order of 50%. Further, none of these approaches appears to address the underlying mechanism of this rare form of cancer.
There is a need in the art to identify novel compounds that can be used to treat or prevent synovial sarcomas in mammals. The present invention meets this need.